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Last Updated: 10/10/18

SPORE in Lymphoma Cancer

University of Iowa/Mayo Clinic

Principal Investigator:
George J. Weiner, M.D.
Thomas E. Witzig, M.D.

Principal Investigator Contact Information

George J. Weiner, MD
Director, Holden Comprehensive Cancer Center
University of Iowa
CE Block Chair of Cancer Research
Professor, Department of Internal Medicine
Department of Internal Medicine
Holden Comprehensive Cancer Center
University of Iowa College of Medicine
200 Hawkins Drive, 5970Z JPP
Iowa City, Iowa 52242
Tel: (319) 353-8620
Fax: (319) 353-8988
Email: george-weiner@uiowa.edu

Thomas E. Witzig
Professor
Mayo Clinic Rochester
200 First Street Southwest
Rochester, MN 55905
Tel: (507) 266-2040
Email: witzig.thomas@mayo.edu

OVERALL ABSTRACT

The University of Iowa/Mayo Clinic Lymphoma SPORE (SPORE) is a dynamic, productive, translational cancer research program based at two comprehensive cancer centers that was first funded in 2002 and competitively renewed in 2007 and 2012. At the center of the ongoing success of the SPORE is the collaborative interaction between investigators at Iowa and Mayo, as well as SPORE basic laboratory, clinical and population science investigators focused on lymphoma. The overall goal of the SPORE is to support innovative, interactive, rigorous translational lymphoma research that leverages the expertise of laboratory, clinical and population science expertise at both institutions. Over the last funding period, the SPORE has been highly productive as demonstrated by identification of new tumor markers and prognostic indices that are being used clinically; scientific findings that led to innovative clinical trials both within and outside the SPORE; multiple publications with many authored by investigators from both institutions; and brisk accrual to translational clinical trials. The SPORE was involved in multiple productive vertical and horizontal collaborations with other national and international academic institutions and organizations. For example, the UI/MC Molecular Epidemiology Resource based in the SPORE is a vital resource for both SPORE research and research projects supported by other grants. It served as the foundation for the funding of the Lymphoma Epidemiology of Outcomes (LEO) Cohort (U01 CA195568) that includes 6 additional institutions, thereby enhancing the scope and diversity of research facilitated by the SPORE. The current proposal includes 4 major research projects. While all of the projects are new, they are based on research results obtained over the past funding period. Project 1 will investigate why the innate immune system (monocyte/macrophage) is suppressed in lymphoma and aims to overcome that suppression with a novel SIRPa-Fc in a phase I trial. Project 2 focuses on enhancing the clinical T-cell response by modifying the lymphoma microenvironment to augment antigen release, presentation of antigen, and T cell activation and combining it with anti-PD1 therapy of NHL. Project 3 is investigating the dysregulated signaling pathways (TRAF3 and GSK3) that regulate glucose hypermetabolism in aggressive lymphoma. They will test a novel GSK3 inhibitor in a phase I trial. Project 4 is a Population Science project will test a combination of germline (host) and somatic (tumor) genomic biomarkers, tumor gene expression, and clinical factors to predict at diagnosis which immunochemotherapy-treated FL patients will have an early clinical failure. The SPORE also includes Developmental Research and Career Enhancement Programs to pursue novel translational concepts in lymphoma research and new investigators through the programs respectively. Finally, the SPORE will enhance the infrastructure that supports translational lymphoma research at both institutions through shared core resources in Administration, Biostatistics and Bioinformatics, Biospecimens, and Clinical Research.

PROJECT 1: ACTIVATING PHAGOCYTIC MACROPHAGES IN NON-HODGKIN LYMPHOMA

Project Co-Leaders:
Stephen M. Ansell, M.D., Ph.D. (basic)
Andrew Lewis Feldman, M.D. (clinical)

Co-Investigators:
Umar Farooq, M.D.
Grzegorz S. Nowakowski, M.D.
Zhi-Zhang Yang, M.D.

The mononuclear phagocyte system is critical in the host's response to pathogens and inflammation, but it is also critical for removing old or malignant cells. In non-Hodgkin lymphoma (NHL), monocytic cells are central components of the innate immune system and CD14+ monocytes in the peripheral blood as well as CD68+ tumor-associated macrophages (TAMs) in tissue influence the prognosis of patients. We have previously shown that CD14+HLADRlow monocytes are increased in the peripheral blood of NHL patients, are induced by IL-10, and profoundly suppresses T-cell function. However, in lymphoma tissue biopsies, we found that many CD68+ TAMs downregulate CD14 expression. While CD14+ TAMs typically expressed common macrophage markers, we found that the CD68+CD14- fraction expressed very few of these markers. To determine whether CD68+CD14- TAMs retained macrophage function, we measured the expression of signal-regulatory protein a (SIRPa), a receptor that inhibits phagocytic function. Based on SIRPa expression, we identified 2 distinct populations of TAMs in sites involved by lymphoma – those that were CD14+SIRPahigh and those that were CD14-SIRPalow/- – but the phagocytic ability and role of these two populations is unknown. SIRPa regulates macrophage-mediated removal of apoptotic cells that upregulate 'eat-me' signals such as calreticulin. The induction of phagocytosis by 'eat-me' signals on tumor cells is countered by 'don't-eat-me' signals such as CD47, which binds macrophage SIRPa to inhibit phagocytosis. CD47 has been shown to be highly expressed on lymphoma cells and is a mechanism by which malignant B-cells protect themselves from phagocytosis by activated macrophages. However, CD47/SIRPa interaction not only regulates phagocytosis but also has a role in modulating T-cell function by enhancing antigen presentation, effectively making the CD47/SIRPa axis an immune checkpoint for the innate immune system. We hypothesize that CD14+SIRPahigh TAMs are highly functional, able to phagocytose malignant cells, present tumor antigens and activate the immune system but are inhibited by CD47. In contrast, CD14-SIRPalow/- TAMs are immature, fail to phagocytose malignant cells and suppress immune function. To improve the outcome of lymphoma patients, the phagocytosis and T-cell activation by both CD14+SIRPahigh and CD14-SIRPalow/- TAMs needs to be augmented. We therefore propose to determine the phagocytic function and immune activation of both CD14+SIRPahigh and CD14-SIRPalow/- TAMs, and determine whether blocking CD47/SIRPa signaling clinically using SIRPa-Fc can enhance the tumor-directed phagocytic function of both populations of TAMs. We anticipate that results from this project will lead not only to a comprehensive understanding of the subtypes of TAMs in lymphoma, but an innovative therapy that harnesses the power of both the innate and adaptive immune systems.

PROJECT 2: MICROENVIRONMENT MODIFICATION AND ANTI-PD1 IMMUNOTHERAPY OF LYMPHOMA

Project Co-Leaders:
George J. Weiner, M.D. (basic)
Brian K. Link, M.D., (clinical)

Co-Investigator:
Haidong Dong, M.D., Ph.D.
Jon C. D. Houtman, Ph.D.
Thomas E. Witzig, M.D.

There have been major advances in recent years enhancing our understanding of the immune response to cancer in general and lymphoma in particular. These advances have impacted on clinical care. The SPORE has a long-standing interest in exploring the unique aspects of the lymphoma microenvironment and how cross-talk between malignant lymphocytes and benign cells contributes to both tumor growth and immunosuppression. SPORE investigators have also explored novel approaches to modifying that microenvironment in a way that enhances antigen presentation and development of an antilymphoma T cell response. T-cell checkpoint blockade is creating great excitement in the overall field of cancer immunotherapy but early phase studies indicate it has suboptimal efficacy as a single agent in non-Hodgkin lymphoma (NHL). Based on this background, the underlying hypothesis of Project 2 is that modifying the lymphoma microenvironment to augment antigen release, uptake and presentation, will increase the lymphoma T cell response and enhance the efficacy anti-PD1 therapy of NHL. We will assess this hypothesis by exploring two specific aims. In the first aim, we will conduct parallel clinical trials combining anti-PD1 therapy with in situ immunization based on intratumoral manipulation of the NHL microenvironment using two distinct strategies. The first strategy involves enhancing antigen release and uptake through node cryoablation followed by intratumoral injection of autologous dendritic cells (DCs). The second strategy involves enhancing antigen presentation and T cell activation through intratumoral injection of virus-like particles (VLPs) containing a Toll Like Receptor 9 (TLR9) agonist. In the second aim, we will evaluate the immune response to these treatments, with a focus on the systemic and intratumoral T cell response. Additional clinical and correlative studies will be designed based on lessons learned from the first set of clinical trials and correlative science. Overall, this project will provide critical information on whether local modification of the microenvironment can enhance the overall systemic immune response and therapeutic efficacy of anti-PD1 therapy, and what approach is best to achieve that goal.

PROJECT 3: TARGETING TUMOR METABOLISM IN LYMPHOMA

Project Leaders:
Gail A. Bishop, Ph.D. (basic)
Thomas E. Witzig, M.D. (clinical)

Co-Investigator:
Daniel Billadeau, Ph.D.
Laura L. Stunz, Ph.D.
Xiaosheng Wu, M.D.

A key feature of lymphomas is the glucose hypermetabolism visualized on FDG-PET imaging. In Project 3 (P3), we are investigating two novel drivers of glucose uptake and utilization. Our preliminary data have revealed that abnormal glucose uptake is a striking feature of B cells deficient in the signaling adaptor protein, TNFR-associated factor 3 (TRAF3). Indeed, ~30% of DLBCL samples have histologic evidence of TRAF3 deficiency. We also found that the multi-functional glycogen synthase kinase (GSK3) is increased in lymphoma cells. B cell TRAF3 in the nucleus promotes the degradation of the cAMP response element-binding protein (CREB) transcriptional complex, and the CREB pro-survival targets Mcl-1, Pim2, and c-Myc are elevated in TRAF3-deficient B cells. In addition, the CREB and NF-?B2 targets Glut1 and hexokinase 2 (HXK2) are also elevated in TRAF3-deficient B cells (as is glucose metabolism) and these cells have increased GSK3 expression. Interfering with GSK3 either by GSK3a/Β knockouts that we developed or by inhibiting the GSK3 with a novel inhibitor 9ING-41 (Actuate Therapeutics) inhibits cell proliferation and induces apoptosis while sparing normal lymphocytes. Thus, there is an important link between the TRAF3 and GSK3 pathways that can potentially be exploited for therapeutic benefit. The overall hypothesis of P3 is that targeting the hyperactive metabolic pathways induced by dysregulation of key signaling pathways in lymphoma cells (TRAF3 deficiency; GSK3 hyperactivity) will provide a new approach to treatment that will enhance established therapies. We have organized this work into 3 Specific Aims.

Aim 1. Determine how TRAF3 deficiency regulates survival and glucose metabolism in pre-malignant and malignant B cells.

Aim 2: Determine the mechanism of action of GSK3 inhibitors in lymphoma cells to develop rational combinations for clinical trials.

Aim 3: Conduct clinical trials of novel inhibitors of tumor metabolism in patients with relapsed lymphoma.

P3 is addressing a significant unmet need in lymphoma biology and therapeutics – understanding and targeting the pathways and mechanisms of the increased glucose metabolism that characterizes almost all aggressive lymphomas at diagnosis and those tumors that fail initial therapy and become refractory. We are approaching this problem in lymphoma biology and treatment with a team experienced in the study of lymphoma biology, signal transduction pathway analysis and clinical trials experience with signal transduction pathway inhibitors. Within the 5 years of this Project we aim to translate new biomarkers and therapies to our patients with glucose-avid lymphomas and spur new research into this important area.

PROJECT 4: GENOMIC PREDICTORS OF EARLY RELAPSE IN IMMUNOCHEMOTHERAPY-TREATED FOLLICULAR LYMPHOMA

Project Leaders:
James R. Cerhan, M.D., Ph.D. (clinical)
Anne J. Novak, Ph.D. (basic)

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma and has a highly variable clinical course. Asymptomatic and low-tumor burden patients can initially be managed by observation or rituximab-monotherapy, while symptomatic and high-tumor burden patients are typically managed at diagnosis with immunochemotherapy (IC) as standard of care. We have shown that IC-treated FL patients who achieve event-free (i.e., no disease progression or re-treatment) status at 24 months after diagnosis (EFS24) have the subsequent life expectancy of the background age and sex matched general population, while those who fail to achieve EFS24 have aggressive disease with poor outcomes. One of the highest priorities for the new NCI-driven paradigm for progress in FL is to address early events in FL including understanding the underlying biology, identifying prognostic and predictive markers, and ultimately developing new therapeutic targets and management strategies for these patients. We hypothesize that a novel combination of germline (host) and somatic (tumor) genomic biomarkers, tumor gene expression, and clinical factors, can improve our ability to predict at diagnosis which IC-treated FL patients will have an early clinical failure, defined as failure to achieve EFS24. To test this hypothesis, we propose to identify, validate and clinically translate germline genetic biomarkers (Aim 1), somatic tumor genomic biomarkers (Aim 2), and gene expression signatures (Aim 3) for failure to achieve EFS24 in IC-treated FL and then develop and validate a novel integrative model (Aim 4) that combines clinical prognostic factors with the biomarkers identified from Aims 1-3. To address these aims, we have assembled an outstanding interdisciplinary team with extensive expertise in the proposed studies. The study leverages the established resources of the Lymphoma SPORE, our horizontal collaborations (LLMPP, SWOG, LYSA), and our leadership in the Lymphoma Epidemiology of Outcomes (LEO) cohort. Our innovative population science project will be the first to comprehensively discover and validate germline genetic, tumor genomic, and gene expression biomarkers for failure to achieve EFS24. We have designed studies that have high internal validity, with a focus on use of large patient cohorts with high quality biospecimens, clinical and outcome data; extensive quality control in biologic sample handling and assays; and multi-stage studies with external validation of results, including use of a geographically and racially/ethnically diverse sample of IC-treated FL patients from the LEO cohort study, which also enhances the generalizability of our results. Our comprehensive approach of discovery-validation and clinical translation should yield a reliable, multiparameter, prognostic model, with potential for major impact on the management of IC-treated FL patients with the ultimate goal of accurate, personalized patient management as well as new insights into lymphoma biology that can also aid in identification of therapeutic targets.

CORE A: ADMINISTRATION

Core Directors:
George J. Weiner, M.D.
Thomas E. Witzig, M.D.

The overall goal of the University of Iowa/Mayo Clinic Lymphoma SPORE (SPORE) Administration Core is to stimulate research in lymphoma and to expedite the translation of discoveries into new and better methods of prevention, detection, and treatment of lymphoma. The Administration Core has served well as the organizational hub of SPORE during the prior funding periods. During the next grant period, it will continue to provide an organizational structure designed to coordinate the activities of the research projects, scientific cores, and developmental programs (Developmental Research Program, Career Enhancement Program) at both institutions. The Administration Core will be responsible for coordinating the function of the SPORE committees including the Executive Committee, the External Advisory Committee, the Internal Advisory Committee and the Patient Advocate Group. Dr. George Weiner and Dr. Thomas Witzig, the SPORE Co-PIs, will serve as Co-Directors of the Administration Core. Weiner and Witzig functioned well as a team during the prior funding periods, and will continue to work collaboratively to provide oversight of SPORE activities. The Administration Core will 1) Provide leadership, organizational support, and financial management for SPORE investigators; 2) Coordinate communication and collaboration between Iowa and Mayo, including support for exchange of ideas between investigators, design of new projects, conduct of translational research, and reporting of translational research findings; 3) Provide information transfer to the scientific community and the public; 4) Provide leadership and organizational support for interactions with the External and Internal Advisory Committees, as well as external and internal review for SPORE research projects; 5) Provide the structure for the establishment and nurture of collaborations to facilitate and expand lymphoma research including interactions between Iowa and Mayo; 6) Work closely with SPORE patient advocates so that they are aware of the progress of the SPORE, and facilitate their ability to provide input at all levels; 7) Foster young investigator development; 8) Communicate with the NCI.

CORE B: BIOSPECIMENS

Core Directors:
Andrew L. Feldman, M.D.
Sergei Syrbu, M.D.

The UI/MC SPORE Biospecimens Shared Resource provides a coordinated, centralized, and dedicated core for the procurement, processing and annotation of biospecimens from patients with lymphoma. The goal of the Biospecimens Core is to procure a variety of biologic specimens on all patients involved in UI/MC SPORE clinical trials and all newly diagnosed lymphoma patients seen at the UI Holden Comprehensive Cancer Center (HCCC) and the Mayo Clinic Cancer Center (MCCC) and enrolled into the Molecular Epidemiology Resource (MER). The specific aims of the Core are: Aim 1) To provide accurate classification of all lymphomas (including chronic lymphocytic leukemia/small lymphocytic lymphoma) from patients enrolled onto SPORE clinical trials and the MER; Aim 2) To collect, process, bank and distribute biologic specimens from Iowa and Mayo lymphoma patients for translational research; Aim 3) To track all biospecimens and ensure linkage to clinical, outcome and related data; and Aim 4) To provide expertise, collaborative support and service for full Projects and Career Enhancement/Developmental Research Awardee research. Specimens are collected and processed under rigorous quality control and distributed to researchers or banked for future SPORE projects. Activities are tracked using a sophisticated database that merges activities at Iowa and Mayo and allows integration with clinical and other data collected in research projects. The Core provides specialized expertise in working with lymphoma biospecimens and is closely aligned with institutional research cores and shared resources, but does not duplicate them. The Core has been highly productive in the last funding cycle and since its inception in 2002. To date, the Core has supported the pathology review and specimen collection from patients on all SPORE clinical trials; 7065 patients enrolled into the MER, and 1237 patients from those outside of the MER eligibility criteria (e.g., relapsed or transformed cases). The entire collection consists of 7958 germline DNA and 5733 serum samples; assembled tissue microarrays in 1790 patients; and banked frozen cells on 1284 patients. New in this funding period, we developed a process to collect stool for gut microbiome analysis, and have collected samples from 153 patients and 47 matched household controls. Also new to the Core is time-of-flight mass cytometry (CyTOF), which allows simultaneous evaluation of >35 proteins on a single-cell level. In planning the next grant cycle, we have worked with all 4 new Projects to ensure that we can meet their biospecimen needs. In addition, the Core will work with young investigators in the Career Enhancement Program on the research design of their proposals so that the appropriate samples can be provided. Lastly, we will provide biospecimens expertise and biobank resources for innovative Developmental Research Proposals. These goals will be met by judicious use of our current Biobank and continued accrual of new patient samples to the bank (MER) and facilitating the collection of trial related samples for Project work.

CORE C: BIOSTATISTICS AND BIOINFORMATICS

Core Director:
Brian J. Smith, Ph.D.

Core Co-Director:
Susan Slager, Ph.D.

Core Investigator:
Yan W. Asmann, Ph.D.

The Biostatistics and Bioinformatics Core (Core) provides collaborative statistical and informatics support to SPORE projects, developmental projects, and other cores. The comprehensive nature of the Core, which will have activities at both Iowa and Mayo, assures each SPORE investigator access to expertise that includes development of study designs and analysis plans, state of the art data analysis and interpretation, data management resources, and abstract and manuscript preparation. The Core builds upon the innovative and time-tested procedures and systems developed by the Division of Biomedical Statistics and Informatics at Mayo Clinic, one of the largest analytical groups in the country whose members have collaborated on more than 8,000 clinical and basic science research studies since 1966, as well as the Holden Comprehensive Cancer Center and the Biostatistics Department at the University of Iowa. For this funding cycle, we added a senior Bioinformaticist staff as a Core member for the proposed sequencing methods in the projects. The Core members will provide design and analysis support across a range of fields, including epidemiological studies, basic sciences including translational and immunologic correlative studies, gene microarray, gene and mutation discovery, expression analysis and genomics, and computational biology. The Core developed the statistical plans for past studies initiated in the SPORE, and has been actively involved in the preparation of statistical plans for the four projects in this application. Support is also provided for the management and integration of existing and newly collected data through consistent and compatible data handling. Areas of support include database development, data form development and processing, data collection and entry, data archiving, quality control, and management of information relating to gene mutation identification and genotyping data for disease linkage experiments. In the past funding periods, the Core developed and maintained the infrastructure to link lymphoma clinical and research databases between University of Iowa and Mayo Clinic. This system is fully functional and allows web-based clinical registration and data entry from both sites into a common database. Furthermore, the Core has and will continue to provide data management for all studies, to monitor adverse events in conjunction with the Clinical Research Core, and to prepare data summaries for manuscript preparation. In summary, strengths of the Biostatistics and Bioinformatics Core are our collaboration with each of the projects and cores, the ability to utilize the established centralized research database as well as the operational and statistical infrastructure already in place in the SPORE, and the breadth of expertise provided by Biostatistics and Bioinformatics personnel.

CORE D: CLINICAL RESEARCH

Core Director:
Thomas Habermann, M.D.

Core Co-Director:
Brian Link, M.D.

The SPORE Clinical Research Core (CRC) has as its primary goal to be the direct translational link between research projects and clinical research emanating from these projects. The CRC is composed of the Clinical Trials Unit and the Molecular Epidemiology Resource (MER). The specific aims are to: 1) coordinate and perform SPORE clinical trial protocols; 2) manage SPORE observational epidemiology protocols and partner with the MER. The CRC provides a critical link between clinical research and the specific projects, cores, and developmental research. The CRC is led by the Director, Thomas M. Habermann, MD, at the Mayo Clinic Cancer Center and a Co-Director Brian Link, MD, at the Holden Comprehensive Cancer Center. A key function of the CRC is to coordinate the development of clinical trials, assist in patient accrual, manage protocol amendments, report adverse events to appropriate agencies, and provide comprehensive quality control on clinical trial data. For the MER, the CRC consents newly diagnosed lymphoma patients, abstracts and enters clinical and epidemiologic data, and systematically follows all MER patients through death. The CRC is linked to other SPORE cores providing SPORE investigators integrated and centralized access for projects. During the last funding cycle the CRC has been very active with 5 trials actively accruing patients and 4 new therapeutic trials initiated; overall 161 patients were accrued to these SPORE trials. Studies of novel agents such as the mTOR inhibitor everolimus were completed and published and moved to combinations with RCHOP in the ALLIANCE National Clinical Trials Network group with promising results. Two trials using the immunostimulatory agent CpG were completed with CpG now incorporated into a new trial in Project 2. During the last funding cycle (through June, 2015), 2391 new patients were enrolled into the MER (cumulative total 7605 patients). Seminal, practice-changing publications in the areas of utility of PET/CT surveillance scans in diffuse large B-cell lymphoma (DLBCL), a new early endpoint - event-free survival (EFS24) for predicting long term DLBCL outcome, and transformation of follicular lymphoma (FL) in the rituximab era all originated from CRC research. The CRC also contributed to large genome-wide association studies in lymphoma, clinical observations in body mass index, complementary alternative medicine and trans fatty acid intake and risk were reported. 86 manuscripts have been published from activities involving this core in the last 4 years of this funding period. The CRC has worked with each of the Project Co-Leaders to plan the new clinical trials included in Projects 1-3 and continued use of the MER in Project 4. The CRC will also work with recipients of the Developmental Research Projects and Career Enhancement Program on any clinical or biomarker trials. The CRC has been vital to success of the SPORE and looks forward to continuing to serve SPORE investigators in the next grant.